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Expression of human tau in hippocampal CA1 neurons from P301S and wild-type mice. Trios of confocal stack projection images taken from T13/NeuN double immunostained-and DAPI counterstained-sections from the CA of P301S (A-C, G-I) and wild-type (D-F, J-L) mice aged 2 (A-F) or 36 weeks (G-L). Images show at both ages the expression of human tau (T13 immunoreactivity, green) in CA1 neurons, as revealed by NeuN immuniostaining (red), in P301 mice in contrast to wild-type mice. Scale bar shown in L indicates 22 m.
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The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulat...
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... P301S and wild-type mice (Kruskal Wallis and Wilcoxon tests, * p ≤ 0.05). AT8-neurons (somatosensory cortex, n = 298 for Grasp65 and n = 269 for MG160; CA1, n = 76 for Grasp65 and n = 188 for MG160) and AT8+ neurons (somatosensory cortex, n = 82 for Grasp65 and n = 85 for MG160; CA1, n = 26 for Grasp65 and n = 75 for MG160). immunostaining (see Fig. 1) and according to previ- 338 ous studies [20], we found no differences between ...
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... In AD, changes in the GA seem to be involved in ineffective protein transport through its membranes, causing the aberrant accumulation of proteins such as APP or Tau. This is a possible explanation for the dysfunction and subsequent cell death observed in this disease [95][96][97]. It has been demonstrated in brain tissue samples and experimental models of AD with Aβ that the abnormal rearrangement of the GA affects cell morphology and several physiological functions [97][98][99]. ...
... This is a possible explanation for the dysfunction and subsequent cell death observed in this disease [95][96][97]. It has been demonstrated in brain tissue samples and experimental models of AD with Aβ that the abnormal rearrangement of the GA affects cell morphology and several physiological functions [97][98][99]. It had been reported that Aβ can alter the GA indirectly through the abnormal acetylation of cytoskeleton proteins, as well as by the induction of Tau hyperphosphorylation and cytoskeleton destabilization, which in turn disrupt intracellular transport [27,100,101]. ...
Amyloid-β oligomers are a cytotoxic structure that is key for the establishment of the beginning stages of Alzheimer’s disease (AD). These structures promote subcellular alterations that cause synaptic dysfunction, loss of cell communication, and even cell death, generating cognitive deficits. The aim of this study was to investigate the cytotoxic effects of amyloid-β1-42 oligomers (AβOs) on the membranous organelles involved in protein processing: the endoplasmic reticulum (ER) and Golgi apparatus (GA). The results obtained with 10 μM AβOs in SH-SY5Y neuroblastoma cells showed that oligomeric structures are more toxic than monomers because they cause cell viability to decrease as exposure time increases. Survivor cells were analyzed to further understand the toxic effects of AβOs on intracellular organelles. Survivor cells showed morphological alterations associated with abnormal cytoskeleton modification 72–96 h after exposure to AβOs. Moreover, the ER and GA presented rearrangement throughout the cytoplasmic space, which could be attributed to a lack of constitutive protein processing or to previous abnormal cytoskeleton modification. Interestingly, the disorganization of both ER and GA organelles exposed to AβOs is likely an early pathological alteration that could be related to aberrant protein processing and accumulation in AD.
... In JNPL3 transgenic mice-which express the P301L mutant of tau, a component of NFTs and paired helical filaments (PHFs)-the Golgi complex was fragmented; however, mitochondria or other membranous organelles appeared normal, indicating that Golgi fragmentation is one of the earliest events that occur during pathogenesis, a finding which has been suggested by other laboratories as well [56][57][58]. Structural deformities in the Golgi complex were also linked to accumulation of phospho-tau in the P301S mouse model of AD [59]. Aging is a major risk factor for neurodegeneration; not surprisingly, increased Golgi fragmentation in neurons was observed with aging. ...
Huntington’s disease (HD) is caused by expansion of polyglutamine repeats in the protein huntingtin, which affects the corpus striatum of the brain. The polyglutamine repeats in mutant huntingtin cause its aggregation and elicit toxicity by affecting several cellular processes, which include dysregulated organellar stress responses. The Golgi apparatus not only plays key roles in the transport, processing, and targeting of proteins, but also functions as a sensor of stress, signaling through the Golgi stress response. Unlike the endoplasmic reticulum (ER) stress response, the Golgi stress response is relatively unexplored. This review focuses on the molecular mechanisms underlying the Golgi stress response and its intersection with cysteine metabolism in HD.
... CA1 also displayed the highest values for the density of Aβ -ir plaques. Previous studies in our laboratory in the CA1 of AD patients have shown that the presence of Aβ -ir plaques leads to local alterations, including changes in pyramidal cell morphology and innervation (e.g., Garcia-Marin et al., 2009;Blazquez-Llorca et al., 2010;Merino-Serrais et al., 2013;Antón-Fernández et al., 2017). Moreover, our previous study-on Aβ -ir plaque distribution in CA1-revealed that most plaques were mainly located in the stratum pyramidale followed by the stratum radiatum, suggesting that the basal and apical dendritic arborization located in these CA1 layers might be severely affected in AD (Furcila et al., 2018). ...
A variety of anatomical alterations have been reported in the hippocampal formation of patients with Alzheimer’s Disease (AD) and these alterations have been correlated with cognitive symptoms in the early stages of the disease. Major hallmarks in AD are the presence of paired helical filaments of tau protein (PHFTau) within neurons, also known as neurofibrillary tangles (NFTs), and aggregates of amyloid-β protein (Aβ) which form plaques in the extracellular space. Nevertheless, how the density of plaques and NFTs relate to the severity of cell loss and cognitive decline is not yet clear. The aim of the present study was to further examine the possible relationship of both Aβ plaques and NFTs with neuronal loss in several hippocampal fields (DG, CA3, CA1, and subiculum) of 11 demented AD patients. For this purpose, using stereological techniques, we compared neuronal densities (Nissl-stained, and immunoreactive neurons for NeuN) with: (i) numbers of neurons immunostained for two isoforms of PHFTau (PHFTau-AT8 and PHFTau-pS396); and (ii) number of Aβ plaques. We found that CA1 showed the highest number of NFTs and Aβ plaques, whereas DG and CA3 displayed the lowest number of these markers. Furthermore, AD patients showed a variable neuronal loss in CA1 due to tangle-related cell death, which seems to correlate with the presence of extracellular tangles.
... However, populations of neurons from AD patients without neurofibrillary tangles were seen to have fragmented GC, and in cells with such structures, the GC is deformed but not fragmented [114]. The GC was reduced in size in neurons from a neurofibrillary tangle P301S tauopathy mouse model [115]. Given that there was no Aβ pathology in this model, the authors deemed that GC damage was not a consequence of it. ...
In most mammalian cells, the Golgi complex forms a continuous ribbon. In neurodegenerative diseases, the Golgi ribbon of a specific group of neurons is typically broken into isolated elements, a very early event which happens before clinical and other pathological symptoms become evident. It is not known whether this phenomenon is caused by mechanisms associated with cell death or if, conversely, it triggers apoptosis. When the phenomenon was studied in diseases such as Parkinson’s and Alzheimer’s or amyotrophic lateral sclerosis, it was attributed to a variety of causes, including the presence of cytoplasmatic protein aggregates, malfunctioning of intracellular traffic and/or alterations in the cytoskeleton. In the present review, we summarize the current findings related to these and other neurodegenerative diseases and try to search for clues on putative common causes.
Tauopathies refer to a group of neurodegenerative disorders caused by the accumulation of insoluble hyperphosphorylated Tau protein in the brain. The inhibition and interruption of Tau aggregation are considered important strategies to ameliorate the neurodegenerative process. Previous work has shown that hexapeptide 306VQIVYK311 (PHF6) located in the repeat domain 3 of Tau protein drives Tau aggregation and itself forms a β-sheet structure similar to those of Tau-oligomers and neurofibrillary tangles (NFTs). In this study, a mirror image phage display technology was used to screen protease-resistant and low-immunogenic d-enantiomeric peptides for their capacity to inhibit Tau aggregation. Following the preparation of d-enantiomeric PHF6 fibrils and M13 phage peptide library biopanning, 7 sets of high specificity peptides were obtained. Through ELISA and competition inhibition assays, we chose a highly specific peptide p-NH with the sequence N-I-T-M-N-S-R-R-R-R-N-H. The molecular docking results showed that p-NH interacted with PHF6 fibrils mainly through van der Waals forces and hydrogen bonding and could inhibit PHF6 aggregation in a d-configuration and concentration-dependent manner. In vitro, p-NH prohibited the formation of PHF6 fibrils and was able to enter into mouse neuroblastoma N2a cells (N2a cells) to inhibit Tau hyperphosphorylation and aggregation. Intranasal administration of p-NH reduced NFTs and improved the cognitive ability of TauP301S transgenic mice. These findings represent a straightforward methodology to find therapeutic peptides with potential applications in tauopathies.
Hibernating mammals undergo torpor periods characterized by a general decrease in body temperature, metabolic rate, and brain activity accompanied by complex adaptive brain changes that appear to protect the brain from extreme conditions of hypoxia and low temperatures. These processes are accompanied by morphological and neurochemical changes in the brain including those in cortical neurons such as the fragmentation and reduction of the Golgi apparatus (GA), which both reverse a few hours after arousal from the torpor state. In the present study, we characterized – by immunofluorescence and confocal microscopy – the GA of cortical astrocytes, oligodendrocytes, and microglial cells in the Syrian hamster, which is a facultative hibernator. We also show that after artificial induction of hibernation, in addition to neurons, the GA of glia in the Syrian hamster undergoes important structural changes, as well as modifications in the intensity of immunostaining and distribution patterns of Golgi structural proteins at different stages of the hibernation cycle.
Mammalian hibernation is a natural process in which the brain undergoes profound adaptive changes that appear to protect the brain from extreme hypoxia and hypothermia. In addition to a virtual cessation of neural and metabolic activity, these changes include a decrease in adult neurogenesis; the retraction of neuronal dendritic trees; changes in dendritic spines and synaptic connections; fragmentation of the Golgi apparatus; and the phosphorylation of the microtubule-associated protein tau. Furthermore, alterations of microglial cells also occur in torpor. Importantly, all of these changes are rapidly and fully reversed when the animals arouse from torpor state, with no apparent brain damage occurring. Thus, hibernating animals are excellent natural models to study different aspects of brain plasticity. The axon initial segment (AIS) is critical for the initiation of action potentials in neurons and is an efficient site for the regulation of neural activity. This specialized structure—characterized by the expression of different types of ion channels and adhesion, scaffolding and cytoskeleton proteins—is subjected to morpho-functional plastic changes upon variations in neural activity or in pathological conditions. Here, we used immunocytochemistry and 3D confocal microscopy reconstruction techniques to measure the possible morphological differences in the AIS of neocortical (layers II–III and V) and hippocampal (CA1) neurons during the hibernation of the Syrian hamster. Our results indicate that the general integrity of the AIS is resistant to the ischemia/hypoxia conditions that are characteristic of the torpor phase of hibernation. In addition, the length of the AIS significantly increased in all the regions studied—by about 16–20% in torpor animals compared to controls, suggesting the existence of compensatory mechanisms in response to a decrease in neuronal activity during the torpor phase of hibernation. Furthermore, in double-labeling experiment, we found that the AIS in layer V of torpid animals was longer in neurons expressing phospho-tau than in those not labeled for phospho-tau. This suggests that AIS plastic changes were more marked in phospho-tau accumulating neurons. Overall, the results further emphasize that mammalian hibernation is a good physiological model to study AIS plasticity mechanisms in non-pathological conditions.
Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer's disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect.
